A human circulating immune cell landscape in aging and COVID-19

Abstract

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtypespecific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.

Keywords

aging / single-cell sequencing / blood / COVID-19 / immune cells

References

[1] Alpert A, Pickman Y, Leipold M, Rosenberg-Hasson Y, Ji X, Gaujoux R, Rabani H, Starosvetsky E, Kveler K, Schaffert S (2019) A clinically meaningful metric of immune age derived from highdimensional longitudinal monitoring. Nat Med 25(3):487–495

[2] Angelidis I, Simon LM, Fernandez IE, Strunz M, Mayr CH, Greiffo FR, Tsitsiridis G, Ansari M, Graf E, Strom TM (2019) An atlas of the aging lung mapped by single cell transcriptomics and deep tissue proteomics. Nat Commun 10(1):963

[3] Bahar R, Hartmann CH, Rodriguez KA, Denny AD, Busuttil RA, Dollé ME, Calder RB, Chisholm GB, Pollock BH, Klein CA (2006) Increased cell-to-cell variation in gene expression in ageing mouse heart. Nature 441(7096):1011–1014

[4] Bi S, Liu Z, Wu Z, Wang Z, Liu X, Wang S, Ren J, Yao Y, Zhang W, Song M (2020) SIRT7 antagonizes human stem cell aging as a heterochromatin stabilizer. Protein Cell 11:483

[5] Bian H, Zheng Z, Wei D, (2020) Meplazumab treats COVID-19 pneumonia: an open-labelled, concurrent controlled add-on clinical trial. medRxiv: 2020.03.21.20040691.

[6] Cheung P, Vallania F, Warsinske HC, Donato M, Schaffert S, Chang SE, Dvorak M, Dekker CL, Davis MM, Utz PJ (2018) Singlecell chromatin modification profiling reveals increased epigenetic variations with aging. Cell 173(6):1385–1397.e14

[7] Ciabattini A, Nardini C, Santoro F, Garagnani P, Franceschi C, Medaglini D (2018) Vaccination in the elderly: The challenge of immune changes with aging. Semin Immunol 40:83–94

[8] Dulken BW, Buckley MT, Navarro Negredo P, Saligrama N, Cayrol R, Leeman DS, George BM, Boutet SC, Hebestreit K, Pluvinage JV (2019) Single-cell analysis reveals T cell infiltration in old neurogenic niches. Nature 571(7764):205–210

[9] Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (2018) Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nat Rev Endocrinol 14(10):576–590

[10] Grabiec AM, Hussell T (2016) The role of airway macrophages in apoptotic cell clearance following acute and chronic lung inflammation. Semin Immunopathol 38(4):409–423

[11] Hakim FT, Gress RE (2007) Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens 70(3):179–189

[12] Hammond TR, Marsh SE, Stevens B (2019) Immune Signaling in Neurodegeneration. Immunity 50:955–974

[13] Han L, Wei X, Liu C, Volpe G, Wang Z, Pan T, Yuan Y, Lei Y, Lai Y, Ward C (2020) Single-cell atlas of a non-human primate reveals new pathogenic mechanisms of COVID-19. bioRxiv.2020.04.10.022103.

[14] He X, Memczak S, Qu J, Belmonte JCI, Liu G (2020) Single-cell omics in ageing: a young and growing field. Nat Metab 2:293

[15] Herzig E, Kim KC, Packard TA, Vardi N, Schwarzer R, Gramatica A, Deeks SG, Williams SR, Landgraf K, Killeen N (2019) Attacking latent HIV with convertibleCAR-T Cells, a highly adaptable killing platform. Cell 179:880–894.e10

[16] Hickman HD, Reynoso GV, Ngudiankama BF, Cush SS, Gibbs J, Bennink JR, Yewdell JW (2015) CXCR3 chemokine receptor enables local CD8(+) T cell migration for the destruction of virusinfected cells. Immunity 42:524–537

[17] Hutten TJ, Thordardottir S, Fredrix H, Janssen L, Woestenenk R, Tel J, Joosten B, Cambi A, Heemskerk MH, Franssen GM (2016) CLEC12A-mediated antigen uptake and cross-presentation by human dendritic cell subsets efficiently boost tumorreactive T cell responses. J Immunol 197(7):2715–2725

[18] Leins H, Mulaw M, Eiwen K, Sakk V, Liang Y, Denkinger M, Geiger H, Schirmbeck R (2018) Aged murine hematopoietic stem cells drive aging-associated immune remodeling. Blood. 132(6):565–576

[19] Li J, Zheng Y, Yan P, Song M, Wang S, Sun L, Liu Z, Ma S, Belmonte JCI, Chan P(2020) A single-cell transcriptomic atlas of primate pancreatic islet aging. Natl Sci Rev

[20] López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153(6):1194–1217

[21] Ma S, Sun S, Geng L, Song M, Wang W, Ye Y, Ji Q, Zou Z, Wang S, He X (2020) Caloric Restriction Reprograms the Single-Cell Transcriptional Landscape of Rattus Norvegicus Aging. Cell 180:984–1001.e22

[22] Martinez-Jimenez CP, Eling N, Chen HC, Vallejos CA, Kolodziejczyk AA, Connor F, Stojic L, Rayner TF, Stubbington M, Teichmann SA (2017) Aging increases cell-to-cell transcriptional variability upon immune stimulation. Science 355(6332):1433–1436

[23] Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ, HLH Across Speciality Collaboration, UK (2020) COVID-19: consider cytokine storm syndromes and immunosuppression. Lancet 395:1033–1034

[24] Merad M, Martin JC (2020) Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages. Nat Rev Immunol 20:355–362

[25] Messaoudi I, Warner J, Fischer M, Park B, Hill B, Mattison J, Lane MA, Roth GS, Ingram DK, Picker LJ (2006) Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci USA 103:19448–19453

[26] Mohrin M, Shin J, Liu Y, Brown K, Luo H, Xi Y, Haynes CM, Chen D (2015) Stem cell aging. A mitochondrial UPR-mediated metabolic checkpoint regulates hematopoietic stem cell aging. Science 347:1374–1377

[27] Mrdjen D, Pavlovic A, Hartmann FJ, Schreiner B, Utz SG, Leung BP, Lelios I, Heppner FL, Kipnis J, Merkler D (2018) Highdimensional single-cell mapping of central nervous system immune cells reveals distinct myeloid subsets in health, aging, and disease. Immunity 48(2):380–395.e6

[28] Onder G, Rezza G, Brusaferro S (2020) Case-Fatality Rate and Characteristics of Patients Dying in Relation to COVID-19 in Italy. JAMA

[29] Ong SM, Hadadi E, Dang TM, Yeap WH, Tan CT, Ng TP, Larbi A, Wong SC (2018) The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence. Cell Death Dis 9(3):266

[30] Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC (2009) Human innate immunosenescence: causes and consequences for immunity in old age. Trends Immunol 30(7):325–333

[31] Pinti M, Appay V, Campisi J, Frasca D, Fülöp T, Sauce D, Larbi A, Weinberger B, Cossarizza A (2016) Aging of the immune system: focus on inflammation and vaccination. Eur J Immunol 46:2286–2301

[32] Pont F, Tosolini M, Fournié JJ (2019) Single-cell signature explorer for comprehensive visualization of single cell signatures across scRNA-seq datasets. Nucleic Acids Res 47:e133

[33] Qi F, Qian S, Zhang S, Zhang Z (2020) Single cell RNA sequencing of 13 human tissues identify cell types and receptors of human coronaviruses. Biochem Biophys Res Commun 526(1):135–140

[34] Radzikowska U, Ding M, Tan G, Zhakparov D, Peng Y, Wawrzyniak P, Wang M, Li S, Morita H, Altunbulakli C (2020) Distribution of ACE2, CD147, CD26 and other SARS-CoV-2 associated molecules in tissues and immune cells in health and in asthma, COPD, obesity, hypertension, and COVID-19 risk factors. Allergy

[35] Rogers KJ, Brunton B, Mallinger L, Bohan D, Sevcik KM, Chen J, Ruggio N, Maury W (2019) IL-4/IL-13 polarization of macrophages enhances Ebola virus glycoprotein-dependent infection. PLoS Negl Trop Dis 13:e0007819

[36] Ruffin N, Gea-Mallorquí E, Brouiller F, Jouve M, Silvin A, See P, Dutertre CA, Ginhoux F, Benaroch P(2019) Constitutive Siglec-1 expression confers susceptibility to HIV-1 infection of human dendritic cell precursors. Proc Natl Acad Sci USA 116(43):21685–21693

[37] Satpathy AT, Granja JM, Yost KE, Qi Y, Meschi F, McDermott GP, Olsen BN, Mumbach MR, Pierce SE, Corces MR (2019) Massively parallel single-cell chromatin landscapes of human immune cell development and intratumoral T cell exhaustion. Nat Biotechnol 37:925–936

[38] Shaulian E, Karin M (2002) AP-1 as a regulator of cell life and death. Nat Cell Biol 4:E131–E136

[39] Son A, Nakamura H, Okuyama H, Oka S, Yoshihara E, Liu W, Matsuo Y, Kondo N, Masutani H, Ishii Y (2008) Dendritic cells derived from TBP-2-deficient mice are defective in inducing T cell responses. Eur J Immunol 38(5):1358–1367

[40] Takenaka MC, Quintana FJ (2017) Tolerogenic dendritic cells. Semin Immunopathol 39(2):113–120

[41] Ulrich H, Pillat MM (2020) CD147 as a Target for COVID-19 Treatment: Suggested Effects of Azithromycin and Stem Cell Engagement. Stem Cell Rev Rep

[42] Van Hove H, Martens L, Scheyltjens I, De Vlaminck K, Pombo Antunes AR, De Prijck S, Vandamme N, De Schepper S, Van Isterdael G, Scott CL (2019) A single-cell atlas of mouse brain macrophages reveals unique transcriptional identities shaped by ontogeny and tissue environment. Nat Neurosci 22(6):1021–1035

[43] Verity R, Okell LC, Dorigatti I, Winskill P, Whittaker C, Imai N, Cuomo-Dannenburg G, Thompson H, Walker P, Fu H (2020) Estimates of the severity of coronavirus disease 2019: a modelbased analysis. Lancet Infect Dis 20(6):669–677

[44] Wang S, Zheng Y, Li J, Yu Y, Zhang W, Song M, Liu Z, Min Z, Hu H, Jing Y (2020) Single-Cell Transcriptomic Atlas of Primate Ovarian Aging. Cell 180:585–600.e19

[45] Watson N, Ding B, Zhu X, Frisina RD (2017) Chronic inflammation-inflammaging- in the ageing cochlea: a novel target for future presbycusis therapy. Ageing Res Rev 40:142–148

[46] Wen W, Su W, Tang H, Le W, Zhang X, Zheng Y, Liu X, Xie L, Li J, Ye J (2020) Immune cell profiling of COVID-19 patients in the recovery stage by single-cell sequencing. Cell Discov 6:31

[47] Wu J, Zhang H, Zheng Y, Jin X, Liu M, Li S, Zhao Q, Liu X, Wang Y, Shi M (2018) The long noncoding RNA MALAT1 induces tolerogenic dendritic cells and regulatory T cells via miR155/dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin/IL10 axis. Front Immunol 9:1847

[48] Yuseff MI, Pierobon P, Reversat A, Lennon-Duménil AM (2013) How B cells capture, process and present antigens: a crucial role for cell polarity. Nat Rev Immunol 13(7):475–486

[49] Zhang X, Liu Z, Liu X, Wang S, Zhang Y, He X, Sun S, Ma S, Shyh-Chang N, Liu F (2019) Telomere-dependent and telomereindependent roles of RAP1 in regulating human stem cell homeostasis. Protein Cell 10:649–667

[50] Zhang W, Zhang S, Yan P, Ren J, Song M, Li J, Lei J, Pan H, Wang S, Ma X (2020) A single-cell transcriptomic landscape of primate arterial aging. Nat Commun 11:2202

[51] Zhou Y, Zhou B, Pache L, Chang M, Khodabakhshi AH, Tanaseichuk O, Benner C, Chanda SK (2019) Metascape provides a biologistoriented resource for the analysis of systems-level datasets. Nat Commun 10:1523

[52] Zhou Y, Fu B, Zheng X, Wang D, Zhao C, Qi Y, Sun R, Tian Z, Xu X, Wei H (2020) Pathogenic T-cells and inflammatory monocytes incite inflammatory storms in severe COVID-19 patients. Natl Sci Rev

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